1, 1, diphenyl-3(n-piperidyl) propane salts of penicillin



Patented Dec. 18, 1951 UNITED STATES 1,1,DIPHENYL-8 (N-PIPERIDYL) PROPANE SALTS F PENICILLIN FrankHbBuckwalter, Dewitt, N. Y., assignor to Bristol Laboratories, 1110., Syracuse, N. Y., a corporation of New York ATNT OFFICE No Drawing. Application October 19, 1948,

Serial No. 55,439 A '4Claims. l The present invention relates to a new amine salt of penicillin, more particularly 1,1,-diphenyl- 3(N-piperidyllpropane salts of penicillin which is capable of exerting a repository antibiotic action.

The new penicillinsalt of the present invention has the following formula wherein Pen designates an acid penicillin radical or an active moiety thereof, capable of forming 'anaddition salt with "1,1,dip'henyl 3i(N-- piperidyl) propane.

A more comprehensive understanding of this invention is obtained by reference to the following examples.

EXAMPLE 1 0.58 gram of 1,1,diphenyl-3(N-piperidyl)propane hydrochloride (1 mole) is dissolved in cc. of water to make a first solution. 0.66 gram of sodium penicillin G (1 mole) are dissolved in 20 cc. of water to yield a solution containing 59,650 units per cc. to make a second solution. The water solution of 1,l,dipheny1-3(N piperi dyDpropane hydrochloride is then added to the water solution of sodium penicillin G and 1.2

grams of a'white crystalline precipitateof 1,1;diphenyl-3(N-piperidyl)propane penicillin is immediately formed having a potency of 600 units .per .mg., theoretical potency 968 units .per mg yield 1.1.gm.

EXAMPLE 2 0.58 gram of 1,1,dipheny1-3(N-piperidyl)propane hydrochloride (1 mole) are dissolved in 10 cc. of water. .066 gram of sodium penicillin G are dissolved in 2.0 cc. of water to yield a solution containing 59,650 units per cc. The solution of 1,1,diphenyl 3(N piperidyl) propane hydrochloride is then reacted with the water solution of sodium penicillin G at pH 6.5. 0.2 gram of a white crystalline precipitate of 1,1,diphenyl-3- (N -piperidyl)propane penicillin was immediately formed having a potency of 763 units per mg.

EXAMPLE 3 1.16 grams of 1,1,diphenyl-3(N-plperidyl) propane hydrochloride (1 mole) are suspended in a separatory funnel in ether and 5 N sodium hydroxide is added, with shaking, to pH 8. The water layer is then separated and the ether layer is dried by adding sodium sulfate. and filtered.

when rabbits are injected with fifty thousand units of 1,1,diphenyl-3(N-piperidyD-propane salt of penicillinG suspended in various vehicles.

1,1 ,dz'phenyl-t"(N-piperidyl) propane salt of penicillin G (225,000 units per co.) in aqueoussolutzcn Blood Level, Hours Rabbit Rabbit 1,1,diphenyZ-3 (N-piperidyl) propane salt .of penicillin G (256,000 units per cc.) plus Na2H2PO4-l2I-I2O in aqueous solution Blood Levels, Hours Rabbit Rabbit No. Wt.

1,1,clz'phenyl-3(N-piperidyl)propane salt of peniczllzn G (257,000 units per cc.) and 5% sodium citrate in aqueous solution Blood Levels, Hours Rabbit Rabbit No. Wt.

1,1,diphenyl-3(N-piperidyl) propane salt of penicillin G plus Tween 40" in aqueous solution Blood Levels, Hours Rabbit Rabbit While the present invention has been described with particular reference to the 1,1,diphenyl- 3(N-piperidyl) propane addition salts of pencillin G it will be understood that 1,1,diphenyl-3(N- piperidyDpropane salts of other penicillins are also included within the scope of this invention. For instance the natural penicillins such as penicillin G, F, X, dihydro F, and K.

EXAMPLE 4 The teachings of this invention may be followed to prepare a salt of pencillin X and 1,1,diphenyl-B-(N-piperidyl) propane. As shown in Examples 1 and 2 above a method may be followed which comprises the step of reacting the soluble salt of penicillin with 1,1,diphenyl-3(N- piperidyl) propane hydrochloride in aqueous solution and recovering the salt of 1,1,diphenyl-3 N- piperidyl) propane penicillin X.

EXAlVDPLE 5 The teachings of this invention may be followed to prepare a salt of penicillin dihydro F and 1,1,diphenyl 3(N piperidyl) propane. As

shown in Examples 1 and 2 above a method may be followed which comprises the step of reacting the soluble salt of penicillin with 1,1,di-

phenyl-3(N-piperidyl) propane hydrochloride in aqueous solution and recovering the salt of 1,1,-

EXAMPLE 6 The teachings of this invention may be followed to prepare a salt of penicillin X and 1,1,diphenyl-3(N-piperidyl) propane. As shown in Example 3 above a method may be followed which comprises the step of reacting the soluble salt of penicillin with 1,1,diphenyl 3(N piperidyl) propane hydrochloride in an organic solvent solution and recovering the salt of 1,1,diphenyl-3(N- piperidyl) propane penicillin X.

EXAMPLE '7 The teachings of this invention may be followed to prepare a salt of penicillin dihydro F and 1,1,diphenyl 3(N piperidyl) propane. As shown in Example 3 above a method may be followed which comprises the step of reacting the soluble salt of penicillin with 1,1,diphenyl-3(N- piperidyl) propane hydrochloride in an organic solvent solution and recovering the salt of 1,1,diphenyl-3(N-piperidyl)propane penicillin dihydro F.

It will be understood that, without departing from the spirit of the invention or the scope of the claims, various modifications may be made in the specific exepdients described. The latter are illustrative only, and not ofiered in a restricting sense, it being desired that only such limitations shall be placed thereon as may be required by the state of the prior art.

I claim:

1. A crystalline salt of penicillin and 1,1,diphenyl-3 (N-piperidyl) propane.

2. A crystalline salt of penicillin G and 1,1,diphenyl-3 (N-piperidyl) propane.

3. A crystalline salt of penicillin X and 1,1,diphenyl-3 (N-piperidyl) propane.

4. A crystalline salt of penicillin dihydro F and 1,1,diphenyl-3 (N-piperidyl propane.

FRANK H. BUCKWALTER.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,493,625 Goldberg et a1. Jan. 3, 1950 2,515,898 Rhodehamel July 18, 1950 OTHER REFERENCES British Report CMR-Br234(PB79,927) received U. S. April 18, 1946, published December 5, 1947, pp. 1-4. 

1. A CRYSTALLINE SALT OF PENICILLIN AND 1,1,DIPHENYL-3(N-PERIDYL) PROPANE. 